NM_133459.4:c.265+28G>C

Variant names:

• chr18-59480158-C-G
• rs1790508
• NM_133459.4:c.265+28G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133459.4(CCBE1):​c.265+28G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 1,389,622 control chromosomes in the GnomAD database, including 266,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33110 hom., cov: 34)
  • Exomes 𝑓: 0.61 (233413 hom.)
• Consequence: CCBE1 NM_133459.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.968
• Publications: 10 publications found

Genes affected

CCBE1 (HGNC:29426): (collagen and calcium binding EGF domains 1) This gene is thought to function in extracellular matrix remodeling and migration. It is predominantly expressed in the ovary, but down regulated in ovarian cancer cell lines and primary carcinomas, suggesting its role as a tumour suppressor. Mutations in this gene have been associated with Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymphatic dysplasia in humans. [provided by RefSeq, Mar 2010]

CCBE1 Gene-Disease associations (from GenCC):

• Hennekam lymphangiectasia-lymphedema syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Hennekam syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 18-59480158-C-G is Benign according to our data. Variant chr18-59480158-C-G is described in ClinVar as Benign. ClinVar VariationId is 262351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCBE1	NM_133459.4	c.265+28G>C		intron_variant	Intron 3 of 10	ENST00000439986.9	NP_597716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCBE1	ENST00000439986.9	c.265+28G>C		intron_variant	Intron 3 of 10	1	NM_133459.4	ENSP00000404464.2

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99782 AN: 151942 Hom.: 33095 Cov.: 34

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.844

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.670

GnomAD2 exomes AF: 0.645 AC: 158385 AN: 245694 AF XY: 0.635

Gnomad AFR exome AF: 0.729

Gnomad AMR exome AF: 0.734

Gnomad ASJ exome AF: 0.569

Gnomad EAS exome AF: 0.842

Gnomad FIN exome AF: 0.591

Gnomad NFE exome AF: 0.606

Gnomad OTH exome AF: 0.623

GnomAD4 exome AF: 0.611 AC: 755824 AN: 1237562 Hom.: 233413 Cov.: 18 AF XY: 0.609 AC XY: 382182 AN XY: 627208

African (AFR) AF: 0.719 AC: 20763 AN: 28888

American (AMR) AF: 0.733 AC: 32343 AN: 44148

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 13840 AN: 24686

East Asian (EAS) AF: 0.831 AC: 31906 AN: 38384

South Asian (SAS) AF: 0.587 AC: 47599 AN: 81118

European-Finnish (FIN) AF: 0.593 AC: 31370 AN: 52932

Middle Eastern (MID) AF: 0.606 AC: 3165 AN: 5226

European-Non Finnish (NFE) AF: 0.596 AC: 542160 AN: 909542

Other (OTH) AF: 0.621 AC: 32678 AN: 52638

GnomAD4 genome AF: 0.657 AC: 99840 AN: 152060 Hom.: 33110 Cov.: 34 AF XY: 0.655 AC XY: 48698 AN XY: 74310

African (AFR) AF: 0.728 AC: 30215 AN: 41504

American (AMR) AF: 0.691 AC: 10561 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1909 AN: 3468

East Asian (EAS) AF: 0.844 AC: 4376 AN: 5182

South Asian (SAS) AF: 0.602 AC: 2905 AN: 4822

European-Finnish (FIN) AF: 0.586 AC: 6176 AN: 10544

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41423 AN: 67950

Other (OTH) AF: 0.662 AC: 1399 AN: 2112

Alfa AF: 0.617 Hom.: 5269

Bravo AF: 0.674

Asia WGS AF: 0.708 AC: 2458 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.43
DANN	Benign	0.45
PhyloP100		-0.97
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1790508; hg19: chr18-57147390; COSMIC: COSV67950975;